Medscape Gastroenterology
The Next Wave of Agents for Treatment of Hepatitis C
William F. Balistreri, MD
November 21, 2013
For several years, the recommended standard of care for patients with chronic hepatitis C virus (HCV) infection consisted of a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). On the basis of understanding of the biology of the virus and identification of proteins involved in HCV replication came the development of agents that inhibited the HCV protease and polymerase enzymes.
A few years ago, the US Food and Drug Administration (FDA) approved 2 direct-acting antiviral agents for the treatment of HCV genotype 1: the NS3 protease inhibitors telaprevir and boceprevir. The American Association for the Study of Liver Diseases guidelines[1] were updated to recommend triple therapy consisting of one of these protease inhibitors given in combination with PEG-IFN and RBV. This recommendation was based on results of clinical trials of this combination, which showed significantly improved sustained virologic response (SVR) rates. Although this triple therapy is generally well tolerated, troublesome side effects occur in many patients. The good news is that the guidelines may once again be revised thanks to the emergence of the next wave of direct-acting antivirals.
Simeprevir and Sofosbuvir
Simeprevir is a potent, once-daily oral investigational NS3/4A protease inhibitor that was shown to be effective when coadministered with standard therapy (PEG-IFN and RBV) for treatment of HCV genotype 1 infection both in treatment-naive patients and in patients who did not respond to standard therapy.[2-10]
Primary efficacy and safety data from clinical trials of simeprevir in patients with genotype 1 chronic HCV infection were in part responsible for the recommended FDA approval of this agent on October 24, 2013. The FDA's Antiviral Drugs Advisory Committee recommendation was unanimous, commenting that the available data overwhelmingly supported approval of the simeprevir, PEG-IFN, and RBV combination for HCV genotype 1 infection in treatment-naive patients and in those who had relapse after previous therapy. The committee reviewed safety and efficacy data from a series of double-blind, placebo-controlled trials -- phase 3 studies of treatment-naive patients and patients with previous relapse, and a phase 2b study involving patients with previous relapse and nonresponders.
For example, simeprevir (TMC435) administered once daily in combination with PEG-IFN and RBV was associated with SVR 12 weeks after the end of treatment (SVR12) in approximately 80% of treatment-experienced (relapsed) genotype 1 chronic hepatitis C patients. The SVR12 rate was less than 40% in patients receiving placebo plus PEG-IFN and RBV. Treatment failure rates and relapse rates were lower in simeprevir recipients than placebo recipients.
Simeprevir was shown to be generally safe and well tolerated, even among patients with advanced liver fibrosis. The most common adverse events were fatigue, headache, and influenza-like illness.
The FDA Advisory Committee did, however, further recommend that patients be screened for the commonly occurring Q80K mutation because simeprevir was found to be less effective in the presence of this mutation. They also recommended that the label should indicate that sunburn is a common side effect. More information about the simeprevir clinical trials can be found at ClinicalTrials.gov.
Soon to follow was the recommended FDA approval of sofosbuvir, a nucleotide analog that inhibits NS5B-directed HCV replication; this agent has also been shown to be highly effective. Sofosbuvir in combination with standard therapy was associated with SVR12 rates of 90% compared with 58% in placebo-treated patients.[11,12]
Both agents will be indicated for treatment of patients with HCV genotype 1, but only in combination with PEG-IFN and RBV. These drugs represent an advance in management -- they promise to be capable of inducing high SVR rates with 1 pill per day, shorter duration of therapy, better tolerability, and no resistance development. The 1-pill-daily regimen simplifies the treatment strategy; however, the cost and side effects are likely to remain high.
A Glimpse of the Future in HCV Treatment
There is an even higher degree of optimism, however, because recent studies may usher in the next wave of treatment strategies for HCV infection. In my opinion, the goal for treatment in terms of efficacy, safety, and tolerability is an IFN-free regimen. Simeprevir is being studied in phase 2 IFN-free trials with and without RBV and in combination with a host of other agents that act synergistically to inhibit HCV replication, and which include all oral regimens. For example, studies in progress suggest that high SVRs can be achieved in patients treated with simeprevir and sofosbuvir together, with and without RBV.
I will end by offering a glimpse of the future. Currently under evaluation in clinical studies are second-generation protease inhibitors and small-molecule drugs that inhibit other viral enzymes. Drug cocktails that target multiple HCV enzymes simultaneously may ultimately become the standard of treatment, as in the current strategy for the management of infection with HIV.
The bottom line is that these exciting advances in antiviral therapy will lead to significant improvements in response rates with reduced adverse effects. These advantages may lower the threshold for HCV treatment for both patients and physicians.
It is important to note, though, that at present only a minority of HCV-infected patients may benefit because of multiple barriers that have been identified and that impede delivery of therapy. A major issue is inadequate case-finding, an obstacle that could be overcome by widespread screening. The Centers for Disease Control and Prevention recently advised enhanced testing; their guidelines state that many persons who test positive for hepatitis C do not receive the necessary follow-up to determine whether they require medical care. Therefore, enhanced efforts to improve awareness, education, and specialist availability are needed.
The high prevalence of HCV infection worldwide should also stimulate expanded efforts in primary prevention, including vaccine development. Perhaps we can soon wave good-bye to HCV!
http://www.medscape.com/viewarticle/814701_3
Friday, November 22, 2013
HCV Newsletter Update: 6 Things You Should Know About Liver Cancer
Is everyone enjoying Friday and daydreaming of the weekend? In our household the little people are looking forward to Saturday afternoon, when a birthday extravaganza will take place at Chuck E. Cheese's. Nana can hardly wait, sort of.
November Newsletter Updates
Each month this blog provides an index of Newsletters containing accurate, timely, cutting-edge information on treating and living with hepatitis C. Today we have a few updates from The American Liver foundation and Hepatitis C News.
All November newsletters, including the above mentioned updates can be found here, on the blog.
American Liver Foundation
Liver Lowdown is the monthly general interest e-newsletter of the American Liver Foundation.
In accordance with the Foundation’s mission, the e-newsletter is disseminated to provide information about the prevention, treatment and cure of liver disease, as well as the organization’s research and advocacy endeavors.
In accordance with the Foundation’s mission, the e-newsletter is disseminated to provide information about the prevention, treatment and cure of liver disease, as well as the organization’s research and advocacy endeavors.
Content includes updates about the Foundation’s educational and signature programs; an in-depth focus on specific types of liver disease, and profiles of liver patients’ and caregivers’ personal experiences
FEATURED This Month
6 Things You Should Know About Liver Cancer
What’s the difference between primary liver cancer and metastatic liver cancer? If you have liver cancer, are there always clear-cut symptoms? And what should you do if you think you’re at risk? Find the answers to these and other important questions.
National Caregivers Month 2013
November is a time each year when we recognize the millions of people who
care for the sick, disabled, and the elderly in the United States. If you’re
caring for someone with liver disease, what can you do to make your life more
manageable and less stressful?
PATIENT STORY
Isaacs's Mystery Illness "Completely Killed his Liver"
Marisela Newcomb vividly remembers the day when she realized her
eight-year-old son, Isaac, was getting sick. But Marisela could never have
guessed how seriously ill he was. Nor could she have anticipated just how
rapidly a potentially lethal form of liver disease would turn her family’s life
upside down.
1-800-GOLIVER (1-800-465-4837)
In addition, questions sent on e-mail to info@liverfoundation.org will be promptly answered.
Stay Connected
Check Us Out On Twitter and Facebook
Hepatitis C news, is an online community for those living with hepatitis C. Join us for news, views and features about hep C, read the real-life experiences of our guest bloggers, and learn about living well with the condition.
A monthly round-up of all things hep C!
Taking a look at recent developments in hep C treatments, a tribute to the legendary musician Lou Reed and the latest contributions from our community here at Hepatitis C News.
Lucinda K. Porter, RN, discusses the importance of a healthy lifestyle.
Taking a look at recent developments in hep C treatments, a tribute to the legendary musician Lou Reed and the latest contributions from our community here at Hepatitis C News.
Lucinda K. Porter, RN, discusses the importance of a healthy lifestyle.
Your Stories
By Larry Gibson
An intensely personal piece from one of our regular contributors, Larry Gibson.
Larry lives in Palm Springs, California, with Dennis Golay, his partner of 32 years and LuLu, their dog. Born in Oklahoma, Larry worked as a fine finish carpenter for many years. He currently works for an organization called AIDS Assistance Program which provides food assistance to low income HIV patients.
An intensely personal piece from one of our regular contributors, Larry Gibson.
Larry lives in Palm Springs, California, with Dennis Golay, his partner of 32 years and LuLu, their dog. Born in Oklahoma, Larry worked as a fine finish carpenter for many years. He currently works for an organization called AIDS Assistance Program which provides food assistance to low income HIV patients.
Gilead's Sovaldi (sofosbuvir) and GSK drugs for HCV and HIV win EU green light
Title: European CHMP Adopts Positive Opinion for Gilead Sciences' Sovaldi® for the Treatment of Chronic Hepatitis C Infection
Date(s): 22-Nov-2013 8:47 AM
For a complete listing of our news releases, please click here
FOSTER CITY, Calif.--(BUSINESS WIRE)--Nov. 22, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion on the company's Marketing Authorisation Application (MAA) for Sovaldi® (sofosbuvir 400 mg tablets), an investigational once-daily oral nucleotide analogue polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection in adults. The CHMP opinion supports the approval of Sovaldi for the treatment of HCV in combination with other agents. The CHMP's recommendation will now be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union (EU).
Chronic HCV is a major cause of liver cancer and liver transplantation in Europe and around the world. The current standard of care for HCV involves up to 48 weeks of therapy with a pegylated interferon (peg-IFN)/ ribavirin (RBV)-containing regimen. These regimens are not always effective and are associated with significant side effects and contraindications with other medicines. Many HCV patients in Europe are not considered appropriate candidates for current treatment options.
The CHMP opinion was adopted following an accelerated review procedure, which is reserved for medicinal products that are expected to be of major public health interest. This assessment does not guarantee marketing authorisation by the European Commission. However, if approved, Sovaldi could be available in the EU in the first quarter of 2014.
The MAA for Sovaldi is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION in which 12 or 16 weeks of Sovaldi-based therapy was found to be superior or non-inferior to currently available treatment options or historical controls, based on the proportion of patients who had a sustained virologic response (were HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV. During the European review, data from two additional Phase 3 studies, VALENCE and PHOTON-1 were filed to the MAA. In the VALENCE study, patients with genotype 3 HCV infection were treated with Sovaldi and RBV for 24 weeks. The PHOTON-1 study evaluated Sovaldi and RBV for 12 weeks in patients with genotype 2 HCV infection co-infected with HIV-1 and for 24 weeks in patients with genotypes 1 or 3 HCV co-infected with HIV-1. In all Phase 3 studies of Sovaldi, no viral resistance to the drug was detected among patients who relapsed following completion of therapy.
To date, nearly 3,000 patients have received at least one dose of Sovaldi in Phase 2 or 3 studies. Sovaldi was well tolerated in clinical studies. Adverse events were generally mild and there were few treatment discontinuations due to adverse events. The most common adverse events occurring in at least 10 percent of patients were consistent with the safety profiles of peg-IFN and RBV and included fatigue, headache, nausea, insomnia, dizziness, pruritis (severe itching) and anemia.
In the United States, an expert advisory committee of the U.S. Food and Drug Administration (FDA) voted unanimously (15-0) on October 25, 2013 that the available data support approval of sofosbuvir. A final decision from the FDA is anticipated by December 8, 2013.
Sovaldi is an investigational product and its safety and efficacy have not been established.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.
Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk of unfavorable results from ongoing and subsequent clinical trials of Sovaldi for HCV. The European Commission, FDA and other regulatory agencies may not approve Sovaldi in the currently anticipated timelines or at all, and any marketing approvals, if granted, may have significant limitations on their use. As a result, Sovaldi may never be successfully commercialized. Further, Gilead may make a strategic decision to discontinue development of Sovaldi if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
Sovaldi is a registered trademark of Gilead Sciences, Inc.
For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
UPDATE 1-Gilead and GSK drugs for HCV and HIV win EU green light
Nov 22 (Reuters) - European regulators have recommended approval of a new drug for hepatitis C treatment from Gilead Sciences and an HIV medicine from GlaxoSmithKline, both of which are expected to be major sellers.
The European Medicine Agency (EMA) said on Friday its committee of experts also gave a green light to an Otsuka tuberculosis drug, following a review of an earlier rejection.
Analysts expect U.S.-based Gilead's sales to surge higher next year on the back of its new so-called HCV treatment known as Sovaldi, or sofosbuvir, for people infected with the liver-destroying hepatitis C virus.
Clinical trials of sofosbuvir in combination with other experimental oral Gilead drugs resulted in more than 95 percent of patients being cured.
GSK's Tivicay, or dolutegravir, is also forecast to be a significant new product for the British drugmaker. It will be sold through the ViiV Healthcare business, in which GSK is the biggest shareholder, alongside Pfizer and Shionogi .
In addition, the European agency recommended approval of a new a new two-in-one diabetes drug called Xigduo from Bristol-Myers Squibb and AstraZeneca.
Recommendations for marketing approval by the EMA's Committee for Medicinal Products for Human Use (CHMP) are normally endorsed by the European Commission within a couple of months.
http://www.reuters.com/article/2013/11/22/europe-medicines-idUSL5N0J72QT20131122
Date(s): 22-Nov-2013 8:47 AM
For a complete listing of our news releases, please click here
FOSTER CITY, Calif.--(BUSINESS WIRE)--Nov. 22, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion on the company's Marketing Authorisation Application (MAA) for Sovaldi® (sofosbuvir 400 mg tablets), an investigational once-daily oral nucleotide analogue polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection in adults. The CHMP opinion supports the approval of Sovaldi for the treatment of HCV in combination with other agents. The CHMP's recommendation will now be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union (EU).
Chronic HCV is a major cause of liver cancer and liver transplantation in Europe and around the world. The current standard of care for HCV involves up to 48 weeks of therapy with a pegylated interferon (peg-IFN)/ ribavirin (RBV)-containing regimen. These regimens are not always effective and are associated with significant side effects and contraindications with other medicines. Many HCV patients in Europe are not considered appropriate candidates for current treatment options.
The CHMP opinion was adopted following an accelerated review procedure, which is reserved for medicinal products that are expected to be of major public health interest. This assessment does not guarantee marketing authorisation by the European Commission. However, if approved, Sovaldi could be available in the EU in the first quarter of 2014.
The MAA for Sovaldi is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION in which 12 or 16 weeks of Sovaldi-based therapy was found to be superior or non-inferior to currently available treatment options or historical controls, based on the proportion of patients who had a sustained virologic response (were HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV. During the European review, data from two additional Phase 3 studies, VALENCE and PHOTON-1 were filed to the MAA. In the VALENCE study, patients with genotype 3 HCV infection were treated with Sovaldi and RBV for 24 weeks. The PHOTON-1 study evaluated Sovaldi and RBV for 12 weeks in patients with genotype 2 HCV infection co-infected with HIV-1 and for 24 weeks in patients with genotypes 1 or 3 HCV co-infected with HIV-1. In all Phase 3 studies of Sovaldi, no viral resistance to the drug was detected among patients who relapsed following completion of therapy.
To date, nearly 3,000 patients have received at least one dose of Sovaldi in Phase 2 or 3 studies. Sovaldi was well tolerated in clinical studies. Adverse events were generally mild and there were few treatment discontinuations due to adverse events. The most common adverse events occurring in at least 10 percent of patients were consistent with the safety profiles of peg-IFN and RBV and included fatigue, headache, nausea, insomnia, dizziness, pruritis (severe itching) and anemia.
In the United States, an expert advisory committee of the U.S. Food and Drug Administration (FDA) voted unanimously (15-0) on October 25, 2013 that the available data support approval of sofosbuvir. A final decision from the FDA is anticipated by December 8, 2013.
Sovaldi is an investigational product and its safety and efficacy have not been established.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.
Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk of unfavorable results from ongoing and subsequent clinical trials of Sovaldi for HCV. The European Commission, FDA and other regulatory agencies may not approve Sovaldi in the currently anticipated timelines or at all, and any marketing approvals, if granted, may have significant limitations on their use. As a result, Sovaldi may never be successfully commercialized. Further, Gilead may make a strategic decision to discontinue development of Sovaldi if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
Sovaldi is a registered trademark of Gilead Sciences, Inc.
For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
UPDATE 1-Gilead and GSK drugs for HCV and HIV win EU green light
Nov 22 (Reuters) - European regulators have recommended approval of a new drug for hepatitis C treatment from Gilead Sciences and an HIV medicine from GlaxoSmithKline, both of which are expected to be major sellers.
The European Medicine Agency (EMA) said on Friday its committee of experts also gave a green light to an Otsuka tuberculosis drug, following a review of an earlier rejection.
Analysts expect U.S.-based Gilead's sales to surge higher next year on the back of its new so-called HCV treatment known as Sovaldi, or sofosbuvir, for people infected with the liver-destroying hepatitis C virus.
Clinical trials of sofosbuvir in combination with other experimental oral Gilead drugs resulted in more than 95 percent of patients being cured.
GSK's Tivicay, or dolutegravir, is also forecast to be a significant new product for the British drugmaker. It will be sold through the ViiV Healthcare business, in which GSK is the biggest shareholder, alongside Pfizer and Shionogi .
In addition, the European agency recommended approval of a new a new two-in-one diabetes drug called Xigduo from Bristol-Myers Squibb and AstraZeneca.
Recommendations for marketing approval by the EMA's Committee for Medicinal Products for Human Use (CHMP) are normally endorsed by the European Commission within a couple of months.
http://www.reuters.com/article/2013/11/22/europe-medicines-idUSL5N0J72QT20131122
Thursday, November 21, 2013
Summary AASLD 2013 - Review Of Several Hepatitis C Interferon-free Regimens
Good evening folks,
As coverage on this years American Association for the Study of Liver Diseases (AASLD) Conference comes to a close, a new summary and commentary on experimental therapies for hepatitis C presented at the meeting is available at three of my favorite HCV websites.
For over a decade, HCV Advocate, HIV and Hepatitis, and NATAP has been an important and familiar presence in the hepatitis C community, providing cutting edge research on HIV and viral hepatitis.
AASLD Coverage - The Peoples Website
The "Peoples Website" also known at HCV Advocate, is a great place for reviewing easy to understand conference coverage, basic information, news and the all-encompassing HCV drug pipeline.
People who are considering HCV treatment will benefit greatly from an overview of the meeting, with study results from several IFN-free combination trials using different direct acting antivirals (DAAs)
Editor-in-Chief, Alan Franciscus, offers commentary on the promising experimental drugs presented at this years meeting, other important posters on cirrhosis and liver cancer are also presented with a quick easy explanation by Mr. Franciscus.
HCV Advocate: Top News from AASLD 2013
AASLD Summary
HIV and Hepatitis also dedicated to providing up-
AASLD - Liver Meeting Ends with Hepatitis C Debrief and the Future of Treatment
Editor-in-Chief and Publisher of HIV and Hepatitis, Liz Highleyman, has written a summary on several interferon-free regimens presented in a "hepatitis debrief" by Mark Sulkowski, Professor of Medicine; Johns Hopkins University School of Medicine.
Excerpt:
The final day of AASLD Liver Meeting, recently held in Washington, DC, featured an overview of the status of new hepatitis C therapies, similarities between HCV and HIV, and a look towards the future of hepatitis C treatment
Looking at genotypes 2 and 3, sofosbuvir plus ribavirin led to 12-week post-treatment sustained virological response (SVR12) rates of 93% for genotype 2 patients treated for 12 weeks and 85% for genotype 3 patients treated for 24 weeks in the VALENCE trial.
This study underscores the growing realization that HCV genotypes 2 and 3 -- traditionally classified together as "easier-to-treat" -- are in fact quite different, with genotype 3 patients benefitting from more intensive therapy.
Development of HCV NS5A replication complex inhibitors has expanded opportunities for interferon-free regimens that target different steps of the viral lifecycle. Though their mechanism of action is not fully understood, they appear to interfere with viral assembly. Several agents in this class, including daclatasvir (BMS-790052), ledipasvir (GS-5885), ABT-267, and MK-8742, have contributed to high cure rates in all-oral regimens with HCV protease or polymerase inhibitors.
Read the complete summary;
AASLD 2013: Liver Meeting Ends with Hepatitis C Debrief and the Future of Treatment
All Commentary/Abstracts commentary and coverage by Liz Highleyman @ hivandhepatitis.com
NATAP stays current by providing news, breaking drug research and treatment information as well as comprehensive reports and developments. Frequently note worthy articles published in peer-reviewed journals which require a yearly fee to subscribe are uploaded by Mr. Levin, for the user to view without the burden of payment.
New Phase II Data from All-Oral Regimens
Jules Levin founder and executive director of National AIDS Treatment Advocacy Project (NATAP) offers commentary, additional resources and slides from Dr. Poordad's presentation; New Phase II Data from All-Oral Regimens which reviews new data on HCV oral IFN-free protease based regimens ABT 450, faldaprevir, MK 5172, simeprevir , asunaprevir, and the much anticipated, soon to be approved - nucleoside based sofosbuvir.
View the complete presentation @ NATAP
All Slides/Abstracts coverage and commentary by Jules Levin @ NATAP
AASLD Coverage
Commentary/Abstracts/Videos @ Healio
CME/CE with commentary by Michael Smith @ MedPage Today
In Case You Missed it
AASLD 2013 Internet Symposium
AASLD 2013 Internet Symposium - ViralEd
The 1.5 hour symposium discussing key studies on current and HCV future drugs, featuring 4 well-known and recognized thought leaders in the HCV field; Fred Poordad, MD ( looking hot in his bow tie), K. Rajender Reddy, MD., Mark Sulkowski, MD., and Nezam H. Afdhal, MD.
Advanced HCV Treatment Topics
Advanced HCV Treatment Topics - Video Discussion Clinical Care Options (CCO)
The program begins with text and video commentary on clinical trial data of investigational agents sofosbuvir and simeprevir in treatment naïve and experienced genotype 3 patients moderated by Fred Poordad, MD, with Nezam H. Afdhal, MD, FRCPI, Douglas T. Dietrich, MD, Paul Y. Kwo, MD, and Norah Terrault, MD, MPH.
*A case-based panel discussion exploring complex management issues in HCV-infected patients
Wednesday, November 20, 2013
Simeprevir Approved for Hepatitis C in Canada
Simeprevir Approved for Hep C in Canada
Medivir AB announced that Health Canada has approved simeprevir for the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non‑pegylated) with ribavirin.
Medivir AB announced that Health Canada has approved simeprevir for the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non‑pegylated) with ribavirin.
Simeprevir received priority review status and is the first treatment for CHC to be approved for once-daily administration with pegylated interferon and ribavirin in Canada.
In Canada, for a drug to receive priority or accelerated review, it must show effective treatment of a serious, life-threatening or severely debilitating disease or condition for which no drug is presently marketed in Canada. Or, it must show a significant increase in efficacy and/or decrease in risk so that the overall benefit/risk profile is improved over existing therapies for a disease that is not adequately managed by a drug already marketed in Canada.
“Canada is the second market where simeprevir has been approved and will be a new agent in the treatment of hepatitis C. The priority review process shows the importance of offering new treatment options also for the hardest to treat patients and we are very happy that both patients and physicians are given new hope,” said Maris Hartmanis, CEO, Medivir.
The approval of simeprevir in Canada is based on four pivotal studies of patients with CHC genotype 1 infection: in treatment-naïve patients (QUEST-1 and QUEST-2), and in patients who have failed prior treatment with pegylated interferon and ribavirin; in PROMISE (prior relapsers) and ASPIRE (prior non-responders).
Results from a pooled analysis of QUEST-1 and QUEST-2 demonstrated that 80% of treatment-naïve patients in the group receiving simeprevir achieved sustained virologic response 12 weeks after the end of treatment (SVR12), compared with 50% of patients in the placebo groups. In PROMISE, 80% of prior-relapser patients in the simeprevir arm of the study achieved SVR12 compared with 37% of patients in the placebo group. Results from ASPIRE demonstrated that use of simeprevir led to sustained virologic response 24 weeks after the end of treatment (SVR24) in 62% of prior partial responder patients and 58% of prior-null responder patients compared with 6% and 15% of prior partial and null-responder patients in the placebo groups, respectively.
Date: November 20, 2013
Source: Medivir
Related - Hot Topics
Simeprevir Approved in Japan and Canada
Simeprevir was approved in Japan September 2013 and in Canada November 20th for the treatment of HCV genotype 1, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non‑pegylated) with ribavirin.
FDA Updates - Sofosbuvir and Simeprevir
Both Drugs Receive Positive FDA reviews by the advisory board
In October the Antiviral Drugs Advisory Committee recommend the approval of Gilead's Sofosbuvir, a nucleotide analog NS5B polymerase inhibitor in combination with just ribavirin for treating adult HCV genotypes 2/3 and in combination with pegylated interferon/ribavirin for genotype 1 and 4 treatment-naive patients and Johnson & Johnson's Simeprevir a protease inhibitor in combination with pegylated interferon and ribavirin for the treatment of adult genotype 1 patients with compensated liver disease, including cirrhosis.
For detailed information please download the FDA review package for sofosbuvir and simeprevir.
The FDA does not have to follow the advice of its panels, but most often does. The U.S. health regulators are scheduled to decide whether to approve sofosbuvir by Dec. 8, and simeprevir by Nov. 27.
Related - Hot Topics
Simeprevir Approved in Japan and Canada
Simeprevir was approved in Japan September 2013 and in Canada November 20th for the treatment of HCV genotype 1, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non‑pegylated) with ribavirin.
FDA Updates - Sofosbuvir and Simeprevir
Both Drugs Receive Positive FDA reviews by the advisory board
In October the Antiviral Drugs Advisory Committee recommend the approval of Gilead's Sofosbuvir, a nucleotide analog NS5B polymerase inhibitor in combination with just ribavirin for treating adult HCV genotypes 2/3 and in combination with pegylated interferon/ribavirin for genotype 1 and 4 treatment-naive patients and Johnson & Johnson's Simeprevir a protease inhibitor in combination with pegylated interferon and ribavirin for the treatment of adult genotype 1 patients with compensated liver disease, including cirrhosis.
For detailed information please download the FDA review package for sofosbuvir and simeprevir.
The FDA does not have to follow the advice of its panels, but most often does. The U.S. health regulators are scheduled to decide whether to approve sofosbuvir by Dec. 8, and simeprevir by Nov. 27.
Tuesday, November 19, 2013
Articles in Press - Muscle Cramps in Liver Disease
Just about everyone will experience muscle cramps, but for people living with liver disease and cirrhosis muscle cramps are more common, causing debilitating pain, adding a significant negative impact to an already difficult disease, according to a recent review "Muscle cramps in liver disease" published in the November issue of Clinical Gastroenterology and Hepatology.
In liver disease, a higher prevalence of muscle cramps were found in cirrhotic patients then in non-cirrhotic patients. Other factors associated with muscle cramps are medications such as lactulose and water pills (diuretics) used to treat cirrhosis. In the review, a study compared cirrhosis patients with congestive heart failure patients, both groups were taking a diuretic, the study resulted in 22% of people with cirrhosis having a significantly higher prevalence of weekly or daily cramps vs 5% of congestive heart failure patients.
As reported;
Interestingly, there was no difference in diuretic use or dosing between the 2 groups, supporting that factors other than diuretic-mediated effects explained the differences. Together, these studies suggest that unique physiological changes may occur in cirrhosis and predispose to the development of cramps.
Muscle Cramps in Liver Disease, will focus on the signs and symptoms of muscle cramps associated with cirrhosis, physical examination and a review of current therapies.
Muscle Cramps in Liver Disease
Shivang S. Mehta Affiliations Corresponding Author InformationReprint requests Address requests for reprints to: Shivang S. Mehta, MD, University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 4.261, Houston, Texas 77030. fax: (713) 500-0635 email address , Michael B. Fallon University of Texas Health Science Center at Houston, Houston, Texas
published online 01 April 2013.
Clinical Gastroenterology and Hepatology
Volume 11, Issue 11 , Pages 1385-1391, November 2013
Muscle cramps are common in patients with liver disease and adversely influence quality of life. The exact mechanisms by which they occur remain unclear, although a number of pathophysiological events unique to liver disease may contribute. Clinical studies have identified alterations in 3 areas: nerve function, energy metabolism, and plasma volume/electrolytes. Treatments have focused on these particular areas with varied results. This review will focus on the clinical features of muscle cramps in patients with liver disease and review potential mechanisms and current therapies.
Muscle cramps are defined as involuntary painful contractions at rest or during sleep of a muscle or muscle group that may last for seconds to minutes and are usually self-limiting.1, 2 Cramps are commonly found in a variety of diseases including liver disease (Table 1).3, 4 Although generally benign, the frequency and severity of cramps may be debilitating and have a significant negative effect on the quality of life (QOL) in affected patients. Despite the association of muscle cramps with liver disease, there is a paucity of information regarding pathogenesis and treatment in these patients.
Table 1. Diseases, Medications, and Physiological Changes Associated With Muscle Cramps
| Idiopathic |
| Neurologic disease |
 Peripheral neuropathy |
| Amyotrophic lateral sclerosis |
| Spinal cord stenosis |
| End-stage disease |
| Liver (cirrhosis) |
| Renal requiring hemodialysis |
| Medications |
| Beta blockers |
| Calcium channel blockers |
| Conjugated estrogens |
| Raloxifene |
| Levalbuterol |
| Naproxen |
| Diuretics |
| Cardiac disease |
| Peripheral vascular disease (claudication) |
| Changes in physiology |
| Exercise induced |
| Pregnancy related |
| Elderly |
| Malignancy |
Prevalence and Clinical Significance
The first report of an association between cirrhosis and muscle cramps was made by Konikoff and Theodor5 in 1986. Of 33 patients with cirrhosis who were studied, 88% were found to have experienced more than 2 cramps in calf muscles within the prior week. Since this report, several subsequent studies have demonstrated a 22%–88% prevalence of muscle cramps in patients with liver disease, depending on differing definitions, frequency, and inclusion criteria (Table 2).5, 6, 7, 8, 9, 10, 11 The majority of studies have found a higher prevalence of cramps in cirrhotic patients relative to control groups. In addition, patients with cirrhosis in comparison with noncirrhotic patients with liver disease have been found to have a greater prevalence of cramps, 31% vs 5%, respectively.7 Abrams et al8 compared patients with cirrhosis with those with congestive heart failure and found a significantly higher prevalence of weekly or daily cramps with cirrhosis (22%) vs patients with congestive heart failure (5%). Interestingly, there was no difference in diuretic use or dosing between the 2 groups, supporting that factors other than diuretic-mediated effects explained the differences. Together, these studies suggest that unique physiological changes may occur in cirrhosis and predispose to the development of cramps.
Table 2. Prevalence of Muscle Cramps in Patients With Cirrhosis
| Author | Year | Number of patients | Prevalence (%) | Comment |
|---|---|---|---|---|
| Konikoff et al5 | 1986 | 33 | 88 | Severe pain occurring in calf muscles several times per week |
| Chao et al52 | 1989 | 331 | 64 | ≥1 cramp per week that occurred mainly during sleep in the lower extremities and lasted for few minutes |
| Konikoff et al6 | 1991 | 29 | 79 | Cirrhotic patients with any severity, duration, or frequency of cramps |
| Kobayashi et al7 | 1992 | 80 | 31 | ≥1 cramp per week |
| Abrams et al8 | 1996 | 92 | 22 | Weekly or daily cramps, either occurring at rest or when awakening a patient from sleep |
| Angeli et al9 | 1996 | 171 | 29 | ≥3 crises per week |
| Baskol et al10 | 2004 | 100 | 56 | ≥1 painful muscle cramp occurring at rest, strong enough to waken a patient from sleep, or occurring once a week during a period of more than 12 months |
| Chatrath et al11 | 2012 | 150 | 67 | Painful, involuntary contraction of skeletal muscles, occurring at rest or strong enough to wake the patient from sleep in the preceding 12 weeks |
The presence of cramps in cirrhosis also adversely influences QOL. Symptom experience in a cohort of 129 patients with cirrhosis found muscle cramps to be the second leading cause of distress and increased intensity of pain.3 Marchesini et al12 surveyed 544 patients with cirrhosis by using the Nottingham Health Profile and the Medical Outcome Study Short Form-36 questionnaires. Muscle cramps were identified as the most frequent variable associated with poor health-related QOL. In fact, muscle cramps were an independent impairment variable in both the physical and mental components of the questionnaire and were a significant factor in impairment in 13 of 14 domains.12, 13
A recent study investigated the QOL of cirrhotic patients experiencing cramps by using the Chronic Liver Disease Questionnaire, a more sensitive and specific survey for determining QOL in this particular group.11, 14, 15 Chatrath et al11 questioned 150 patients with cirrhosis and cramps and found significantly lower Chronic Liver Disease Questionnaire scores that were due to lower domain scores in abdominal symptoms, fatigue, systemic symptoms, activity, emotional functions, and worry relative to cirrhotic patients without cramps. These studies suggest that muscle cramps take a mental and physical toll on affected cirrhotic patients.
Pathophysiology
The pathophysiological mechanisms of muscle cramps in patients with cirrhosis are not clearly elucidated. However, a number of mechanisms have been considered and explored. Potential mechanisms may be divided into alterations in 3 overlapping areas: (1) nerve function, (2) energy metabolism, and (3) plasma volume and electrolytes (Figure 1).
Nerve Function
Energy Metabolism
The liver has a central role in amino acid and protein metabolism and is responsible for the deamination and modification of amino acids and the synthesis of amino acids into proteins.22 The regulation of amino acid and protein metabolism is altered in those with cirrhosis, which is reflected by decreased plasma and skeletal muscle concentrations of taurine (the most abundant amino acid in skeletal muscle). Altered taurine concentrations appear to result from both decreased production related to an imbalance in the ratio of branched-chain amino acids to aromatic amino acids and increased release from muscle.22, 23, 24 Taurine concentrations influence the function of a number of critical ion channels, including voltage-dependent chloride channels and calcium-activated sodium and potassium channels, which modulate striated fiber electrical activity and stabilize the sarcolemma.25, 26 The net result of taurine deficiency is a decrease in the threshold potential and hyperexcitability of skeletal muscle.27 Yamamoto et al28 directly measured the mean plasma taurine level in cirrhotic patients with and without muscle cramps in comparison with controls by using high-performance chromatography and found significant differences. The mean plasma taurine level in cirrhotic patients with cramps was 56.9 nmol/mL, whereas in those without cramps it was 79.3 nmol/mL, and healthy controls had a level of 90.1 nmol/mL. These findings support that taurine deficiency may alter skeletal muscle electrical properties, thereby predisposing these patients to cramps.
Another potential contributor to altered energy metabolism in cirrhosis is a reduction in adenosine triphosphate (ATP) production. Moller et al29 performed skeletal muscle biopsies in 10 cirrhotic patients and found a reduction in ATP, phosphocreatine, and total adenine nucleotide levels. A lack of ATP could diminish the cycling process of actin and myosin cross-bridging, causing prolonged muscle contraction particularly in the presence of abnormal electrical activity.
Plasma Volume, Electrolytes, and Zinc
Electrolyte abnormalities including hyponatremia, hypokalemia, and hypomagnesemia as well as shifts in plasma volume that can influence intracellular concentrations of electrolytes or cause hypovolemia have been implicated as factors in producing cramps.30, 31, 32 Angeli et al9 sought to determine whether plasma volume, plasma renin activity (PRA), mean arterial pressure (MAP), serum albumin, and electrolyte concentrations affected the occurrence of muscle cramps in 224 patients with cirrhosis with and without ascites compared with 194 healthy controls. In multivariate analysis only higher PRA, presence of ascites, and lower MAP were predictors of cramps occurring in patients with cirrhosis because serum electrolyte concentrations of sodium, potassium, phosphorus, and magnesium had no effect on cramp occurrence. These studies would support that shifts in plasma volume may influence cramps, possibly by decreasing perfusion to nerves. In the same year, Abrams et al8 compared 92 patients with cirrhosis, 40 with chronic hepatitis without evidence of cirrhosis, and 40 patients with congestive heart failure to control for diuretic use. This study found similar results to that of Angeli et al in that no clinically significant difference in serum electrolyte concentrations was observed between cirrhotic patients with and without cramps. Also in multivariate analysis, diuretic use was not a significant contributor for the occurrence of cramps (P = .48). Subsequent studies confirmed these results and found no significant difference in the concentrations of zinc, sodium, potassium, magnesium, or calcium in cirrhotic patients with and without cramps.10, 11 Together, these results suggest that shifts in plasma volume may contribute to cramps, whereas serum electrolyte concentrations and diuretic use do not directly influence the frequency of cramps in patients with cirrhosis. However, intracellular concentrations of electrolytes could influence muscle excitability and have not been measured in cirrhotic patients with and without cramps.
Treatment
Therapies for muscle cramps in cirrhosis are generally directed at the 3 potential pathophysiological mechanisms or are empiric (Table 3).
Table 3. Potential Mechanisms of Action of Agents Used to Treat Cramps in Cirrhotic Patients
| Agent | Mechanism of action | Route of administration (dose studied) | Side effects |
|---|---|---|---|
| Quinidine sulfate | Increases the muscle refractory period and decreases the excitability of motor end plate to nerve stimulation | Oral (400 mg daily) | Mild diarrhea, thrombocytopenia, cardiac arrhythmias, cinchonism |
| Vitamin E | Important antioxidant in the cell membrane that acts to decrease circulating free radicals | Oral (200 mg 3 times daily) | None reported |
| Human albumin | Expansion of plasma volume and improvement of hypovolemia and possible subsequent ischemia to neurons | Intravenous (100 mL 25% human albumin solution) | None reported |
| Zinc | Unknown | Oral (220 mg twice daily) | Mild diarrhea |
| Taurine | Sarcolemma stabilization via calcium channel regulation and conductance | Oral (3 g daily) | None reported |
| Eperisone hydrochloride | Centrally acting muscle relaxant | Oral (150–300 mg daily) | Dizziness, fatigue, and epigastric discomfort |
| Branched-chain amino acids | Increases serum albumin and taurine production | Oral (4 g granules 3 times daily) | None reported |
Nerve Function Vitamin E
Vitamin E is a fat-soluble vitamin with α-tocopherol as the major biologically active form. It has potent antioxidant effects and also stabilizes the phospholipid bilayer of cell membranes.33 Vitamin E deficiency in animal models results in myocyte necrosis and in humans in myopathy.34, 35 Von Herbay et al36 demonstrated that lower serum vitamin E levels were found in alcoholic liver disease, hemochromatosis, and Wilson's disease compared with healthy controls. Two additional studies have reported on treatment with vitamin E for cramps in patients with cirrhosis. Konikoff et al6 recruited 29 patients with cirrhosis and found 23 with cramps. Those with cramps had significantly lower serum vitamin E levels than those without cramps (6.3 ± 3.2 vs 11.5 ± 4.8 μg/mL, P = .01). Thirteen subjects were treated with vitamin E (200 mg 3 times daily for 4 weeks) and had significant improvement on the basis of a scoring system assessing cramp severity, frequency, and duration. A subsequent pilot randomized, double-blind, placebo-controlled crossover study in 9 adult cirrhotic subjects found no statistical significance between vitamin E and placebo in the frequency (P = .98), duration (P = .93), or severity of muscle cramps (P = .57).37 However, treatment dosage and duration of treatment in the vitamin E arm were not reported. Both studies identified no significant side effects to treatment. Further studies are needed to assess whether vitamin E is effective in treating cramps and to define whether serum vitamin E levels might predict responsiveness.
Quinine sulfate
Quinine, an alkaloid powder derived from the bark of the cinchona tree, was first reported as a treatment for muscle cramps in patients without cirrhosis in the 1940s.38, 39 Although the mechanism of action of quinine in cramps is not elucidated, it is believed to reduce the excitability of the motor nerve by prolonging the refractory period of muscle to repetitive stimuli.40, 41 A number of studies and a recent meta-analysis comparing quinine with vitamin E for the treatment of muscle cramps in noncirrhotic subjects found improvement with both agents but no significant difference in efficacy between them.2 A single study has investigated quinidine sulfate (optical isomer of quinine) for the treatment of muscle cramps in cirrhosis. Lee et al42 conducted a single-blind study in 31 cirrhotic patients with a history of cramps at least twice weekly for the preceding year. Sixteen patients received quinidine sulfate 200 mg twice daily for 4 weeks, and these patients had a significant reduction in the number of episodes of cramps during treatment (14.4 ± 1.7 to 4.4 ± 1.1, P < .0001) relative to the placebo group (11.8 ± 1.0 to 11.5 ± 1.5, P > .05). Mild diarrhea (31%) was the only side effect reported in the treatment group. Quinine is no longer available over-the-counter in the United States because of rare significant adverse effects including thrombocytopenia, cardiac arrhythmias, hemolysis, and cinchonism.43 Therefore, the risk-benefit ratio for using quinine/quinidine in the treatment of cramps in cirrhosis is unfavorable.
Eperisone hydrochloride
Eperisone hydrochloride is a centrally acting muscle relaxant that appears to suppress sympathetic stimulation in skeletal muscle.44 Kobayashi et al7 treated 21 cirrhotic patients who reported having cramps more than once weekly in an open-label study with eperisone hydrochloride (150–300 mg) daily for 8 weeks. A complete disappearance of symptoms was found in 11 patients (61%), with decreased frequency in 6 patients (33%) and 1 patient with no change in symptoms. Adverse effects included epigastric discomfort, fatigue, and dizziness. Although there did appear to be a decrease in cramp frequency with treatment, the study was not blinded, there were significant side effects, and no long-term follow up data are available.
Energy Metabolism
Taurine
Three small open-label studies have evaluated taurine as a treatment for muscle cramps in cirrhosis. In the first study, 12 nonalcoholic cirrhotic patients were given 6 g taurine 3 times daily for 4 weeks.23 Eight patients had complete resolution of cramps, and 4 patients had a significant decrease in cramp severity by 1 month. No adverse effects were observed. In a second study, 35 cirrhotic patients were treated with 3 g taurine daily for 4 weeks. Twenty-five patients (71.4%) had significant improvement in cramps, with 13 (37.1%) having complete disappearance of symptoms. A third study by Yamamoto et al28 extended the prior studies by comparing plasma taurine concentrations in 15 cirrhotic patients with cramps and 13 without cramps. Plasma taurine concentrations were significantly lower in the cirrhotic patients with cramps. Nine of the cirrhotic patients with cramps were given 3 g taurine daily for 4 weeks, and all had increased plasma taurine levels and reported significant improvement in symptoms, with 6 (67%) reporting complete resolution. No adverse effects were reported. These encouraging studies support that taurine may be a useful agent to treat muscle cramps in cirrhotic patients, particularly in those with low plasma taurine levels. However, larger double-blind, placebo-controlled studies are needed to confirm these findings.
Branched-chain amino acids
Administration of branched-chain amino acids (isoleucine, leucine, and valine) in cirrhosis has been reported to improve serum albumin levels, increase taurine production, and possibly decrease progression of liver disease.45, 46, 47 Two studies have explored the possibility that branched-chain amino acid supplementation might also decrease the frequency of muscle cramps in patients with cirrhosis. Sako et al48 treated 8 patients in an open-label study with nocturnal branched-chain amino acid supplements for 3 months and found a significant increase in serum albumin levels and a significant decrease in frequency of cramps relative to pretreatment values (7.4 ± 2 to 0.3 ± 0.5 times/week, P < .0001). Hidaka et al49 performed a small multicenter randomized study in 37 patients that compared daytime and nocturnal branched-chain amino acid supplementation for 3 months. The frequency of muscle cramps significantly decreased in both groups (P = .004), and no adverse effects were reported. These preliminary studies suggest that branched-chain amino acid supplementation may be an effective treatment for muscle cramps in cirrhosis.
Plasma Volume, Electrolytes, and Zinc
Human albumin
A single small crossover study has reported the use of intravenous albumin for treatment of muscle cramps in cirrhosis.9 Twelve patients with compensated liver disease were given placebo or 100 mL 25% human albumin solution intravenously once weekly for 4 weeks. Compared with placebo administration, albumin significantly decreased cramp frequency (2.5 ± 2.9 vs 6.2 ± 2.5, P < .001) and also decreased PRA and improved MAP. These findings suggest that intravenous albumin may decrease cramps in cirrhosis, possibly by increasing intravascular plasma volume. From a practical perspective, the cost and requirement for intravenous access to deliver albumin limit feasibility as a therapy.
Electrolytes and zinc
Serum electrolyte concentrations do not differ in cirrhotic patients with and without cramps. Therefore, studies have not focused on electrolyte replacement as a treatment for cramps. Empiric replacement of low serum electrolyte concentrations in cirrhotic patients with cramps is common, although whether this improves symptoms is unknown. Zinc has been used as empiric treatment for muscle cramps in cirrhosis.50 In a small study of 12 patients with low serum zinc concentrations (<70 μg/dL), oral zinc sulfate 220 mg twice daily for 12 weeks significantly decreased cramp frequency and increased serum zinc concentrations (40 ± 4.09 vs 63.8 ± 5.11 μg/dL, P = .0001). One patient reported mild diarrhea as an adverse effect. A subsequent study found low serum zinc concentrations in cirrhotic patients relative to healthy controls but no difference in levels between cirrhotic patients with and without cramps.10 These studies raise the possibility that zinc supplementation may be beneficial in cirrhotic patients with low serum zinc concentrations, but more data are needed.
Approach to the Cirrhotic Patient With Cramps
In patients with cirrhosis who present with muscle pain, a careful history should be obtained to differentiate cramps (spontaneous, chronic, and often nocturnal) from other causes of pain (Figure 2).
In particular, new-onset persistent muscle pain should trigger consideration of other diagnoses such as rhabdomyolysis, myositis, or acute kidney injury for which laboratory tests to assess electrolytes and other parameters would be appropriate. A standardized cramp questionnaire may be useful to define the presence and severity of cramps and in assessing the effectiveness of treatments (Figure 3).11, 51
In those found to have cramps, consideration of etiologies other than cirrhosis should be contemplated (Table 2). Serum electrolyte concentrations are frequently measured and, when low, repleted. When cramps related to cirrhosis are present and are clinically significant, an attempt at treatment is reasonable. Although large controlled trials are lacking, the use of over-the-counter, inexpensive agents with favorable side effect profiles (branched-chain amino acids, taurine, and vitamin E) may be considered. Branched-chain amino acids and taurine may have the greatest potential benefit on the basis of effects on proposed mechanisms for cramps and on possible improvement in nutritional parameters. Other treatments as outlined previously are not currently recommended because of ineffectiveness, expense, and/or the risk of side effects.
Approach to the cirrhotic patient with cramps. CK, creatinine kinase; CRP, C-reactive protein; CQ, cramp questionnaire; EMG, electromyogram; ESR, erythrocyte sedimentation rate.
Click To Enlarge
Cramp Questionnaire. Clinically significant cramp (frequency of cramps/week × severity of cramps) >12.
Click To Enlarge
Conclusion
Muscle cramps in patients with liver disease are common and are associated with a negative impact on QOL. Although a number of mechanisms for cramps in liver disease have been postulated and have been targeted by medical therapies, a clear picture of the causal events has not emerged. Several agents have shown benefit in small uncontrolled studies, although large randomized controlled trials are lacking. Treatments such as branched-chain amino acids and taurine may have the greatest potential benefit because they target proposed mechanisms and may also improve nutritional status.
http://www.cghjournal.org/article/S1542-3565(13)00414-X/fulltext#tbl1
Monday, November 18, 2013
AbbVie HCV Oral Combo Nearly Perfect
AM Press Release: AbbVie- Interferon-Free, 12-wk Regimen, 96 Percent SVR12 Genotype 1 Hepatitis C Patients
Infectious Disease
HCV Oral Combo Nearly Perfect
Published: Nov 18, 2013
A four-drug oral regimen for hepatitis C (HCV) achieved near-perfect cure rates in a large clinical trial, according to the company developing the drugs.
First results from the phase III SAPPHIRE-1 study show that 96% of treated patients had undetectable virus 12 weeks after the end of therapy, according to a release from AbbVie, of North Chicago, Ill.
That endpoint -- a virologic response sustained for 12 weeks after stopping treatment , or SVR12 -- is regarded as a cure, since few patients relapse after that point.
While the company released some details, results of the 631-patient study have not yet been presented at scientific meetings or in peer-reviewed journals.
The SAPPHIRE-1 study is one of six phase III trials evaluating three so-called direct-acting agents being developed by AbbVie -- ABT-333, a non-nucleoside polymerase inhibitor; ABT-450/r, an HCV NS3/4A protease inhibitor boosted with the protease inhibitor ritonavir (Norvir); and ABT-267, which blocks the viral nonstructural protein NS5A.
The latter two drugs were given in a fixed-dose combination.
All patients in the treatment arm were also given ribavirin, an oral medication that, with pegylated interferon, forms the backbone of standard therapy. But interferon, which is given by injection and has severe side effects, was not used, the company said.
The goal of much recent investigation has been to develop all-oral regimens that do not include either ribavirin or interferon, and several of the other phase III trials directed by AbbVie are testing only the company's three direct-acting agents.
Study participants had genotype 1 HCV, the most prevalent form of the virus, and no evidence of liver cirrhosis; 473 patients were randomly assigned to the treatment arm for 12 weeks and the remaining 158 got placebos.
After the initial 12-week period, placebo patients were switched to open-label treatment with the four drugs for another 12 weeks. The company did not report outcomes for that treatment period.
Among the 473 patients in the treatment arm, 455 reached an SVR12 in an intent-to-treat analysis where patients with missing data were considered failures.
There was a slight difference in outcomes based on genotype 1 subtype, the company release said: 148 of the 151 patients with genotype 1b achieved SVR12 compared with 307 of the 322 with genotype 1a, or 98% versus 95%.
The company said the most commonly reported adverse events were fatigue, headache, and nausea; the proportion of patients stopping the trial because of adverse events was 0.6% in each arm.
Among patients in the active arm, the combined rate of virologic relapse (after treatment and before 12 weeks) or breakthrough (during therapy) was 1.7%.
http://www.medpagetoday.com/InfectiousDisease/Hepatitis/42971
From (Reuters)
AbbVie's hepatitis C treatment helps 96 pct of patients in trial
AbbVie Inc said a late-stage trial of its experimental oral hepatitis C treatment showed about 96 percent of patients had no detectable levels of the virus after 12 weeks.
AbbVie shares rose 3 percent. Shares of Enanta Pharmaceuticals Inc, which collaborates with AbbVie on one of the drugs included in the treatment, rose 4 percent.
The trial is being watched closely because of the potential of the treatment, 3D regimen, to eliminate the need for the injectable drug interferon, which can have debilitating side effects.
Analysts said the "high efficacy" seen in the trial was in line with market expectations but underlined the increasingly competitive landscape.
"Thus far AbbVie looks competitive but still key data to come," UBS analyst Marc Goodman wrote in a note.
AbbVie, the pharmaceuticals business spun off by Abbott Laboratories early this year, said it was on track for regulatory submissions for the treatment in the second quarter of 2014.
"We conservatively forecast AbbVie's HCV regimen to produce $192 million in 2015, and reach peak sales of $950 million in 2018," BMO Capital Markets analyst Alex Arfaei wrote in a note.
Gilead Sciences Inc's experimental hepatitis C drug sofosbuvir is awaiting a decision from the U.S. Food and Drug Administration.
Bristol-Myers Squibb Co also has advanced all-oral clinical trial programs in late-stage development. But Gilead is widely seen to be leading the race.
AbbVie's trial, named Sapphire-I, is the first of six late-stage trials testing AbbVie's interferon-free treatment.
AbbVie's 3D regimen combines three drugs along with an existing medicine, ribavirin.
The trial tested the treatment in 631 patients, who had received no prior treatment and had no signs of liver cirrhosis. They had the genotype 1 variant of the infection, which accounts for roughly 70 percent of hepatitis C cases.
AbbVie's shares were up about 2 percent at $49.35 in morning trading on the New York Stock Exchange.
(Reporting by Esha Dey in Bangalore; Editing by Don Sebastian)
Infectious Disease
HCV Oral Combo Nearly Perfect
Published: Nov 18, 2013
A four-drug oral regimen for hepatitis C (HCV) achieved near-perfect cure rates in a large clinical trial, according to the company developing the drugs.
First results from the phase III SAPPHIRE-1 study show that 96% of treated patients had undetectable virus 12 weeks after the end of therapy, according to a release from AbbVie, of North Chicago, Ill.
That endpoint -- a virologic response sustained for 12 weeks after stopping treatment , or SVR12 -- is regarded as a cure, since few patients relapse after that point.
While the company released some details, results of the 631-patient study have not yet been presented at scientific meetings or in peer-reviewed journals.
The SAPPHIRE-1 study is one of six phase III trials evaluating three so-called direct-acting agents being developed by AbbVie -- ABT-333, a non-nucleoside polymerase inhibitor; ABT-450/r, an HCV NS3/4A protease inhibitor boosted with the protease inhibitor ritonavir (Norvir); and ABT-267, which blocks the viral nonstructural protein NS5A.
The latter two drugs were given in a fixed-dose combination.
All patients in the treatment arm were also given ribavirin, an oral medication that, with pegylated interferon, forms the backbone of standard therapy. But interferon, which is given by injection and has severe side effects, was not used, the company said.
The goal of much recent investigation has been to develop all-oral regimens that do not include either ribavirin or interferon, and several of the other phase III trials directed by AbbVie are testing only the company's three direct-acting agents.
Study participants had genotype 1 HCV, the most prevalent form of the virus, and no evidence of liver cirrhosis; 473 patients were randomly assigned to the treatment arm for 12 weeks and the remaining 158 got placebos.
After the initial 12-week period, placebo patients were switched to open-label treatment with the four drugs for another 12 weeks. The company did not report outcomes for that treatment period.
Among the 473 patients in the treatment arm, 455 reached an SVR12 in an intent-to-treat analysis where patients with missing data were considered failures.
There was a slight difference in outcomes based on genotype 1 subtype, the company release said: 148 of the 151 patients with genotype 1b achieved SVR12 compared with 307 of the 322 with genotype 1a, or 98% versus 95%.
The company said the most commonly reported adverse events were fatigue, headache, and nausea; the proportion of patients stopping the trial because of adverse events was 0.6% in each arm.
Among patients in the active arm, the combined rate of virologic relapse (after treatment and before 12 weeks) or breakthrough (during therapy) was 1.7%.
http://www.medpagetoday.com/InfectiousDisease/Hepatitis/42971
From (Reuters)
AbbVie's hepatitis C treatment helps 96 pct of patients in trial
AbbVie Inc said a late-stage trial of its experimental oral hepatitis C treatment showed about 96 percent of patients had no detectable levels of the virus after 12 weeks.
AbbVie shares rose 3 percent. Shares of Enanta Pharmaceuticals Inc, which collaborates with AbbVie on one of the drugs included in the treatment, rose 4 percent.
The trial is being watched closely because of the potential of the treatment, 3D regimen, to eliminate the need for the injectable drug interferon, which can have debilitating side effects.
Analysts said the "high efficacy" seen in the trial was in line with market expectations but underlined the increasingly competitive landscape.
"Thus far AbbVie looks competitive but still key data to come," UBS analyst Marc Goodman wrote in a note.
AbbVie, the pharmaceuticals business spun off by Abbott Laboratories early this year, said it was on track for regulatory submissions for the treatment in the second quarter of 2014.
"We conservatively forecast AbbVie's HCV regimen to produce $192 million in 2015, and reach peak sales of $950 million in 2018," BMO Capital Markets analyst Alex Arfaei wrote in a note.
Gilead Sciences Inc's experimental hepatitis C drug sofosbuvir is awaiting a decision from the U.S. Food and Drug Administration.
Bristol-Myers Squibb Co also has advanced all-oral clinical trial programs in late-stage development. But Gilead is widely seen to be leading the race.
AbbVie's trial, named Sapphire-I, is the first of six late-stage trials testing AbbVie's interferon-free treatment.
AbbVie's 3D regimen combines three drugs along with an existing medicine, ribavirin.
The trial tested the treatment in 631 patients, who had received no prior treatment and had no signs of liver cirrhosis. They had the genotype 1 variant of the infection, which accounts for roughly 70 percent of hepatitis C cases.
AbbVie's shares were up about 2 percent at $49.35 in morning trading on the New York Stock Exchange.
(Reporting by Esha Dey in Bangalore; Editing by Don Sebastian)
AbbVie- Interferon-Free, 12-wk Regimen, 96 Percent SVR12 Genotype 1 Hepatitis C Patients
Related Investment Commentary: AbbVie steps closer to FDA filing as first hep C PhIII delivers promising results
Press Release
AbbVie Releases First of Six Phase III Results from Investigational All-Oral, Interferon-Free, 12-week Regimen, Showing 96 Percent SVR12 in Genotype 1 Hepatitis C Patients New to Therapy
- Confirms results of phase II studies, with consistent virologic response and tolerability profile
- Largest all-oral, interferon-free clinical program in genotype 1 (GT1) patients to date(1)
- On track for major regulatory submissions in Q2 2014
- Worldwide, about 160 million people are chronically infected with hepatitis C(2), most with GT1
AbbVie's multinational HCV program is the largest all-oral, interferon-free clinical program in GT1 patients being conducted to date. GT1 (with subtypes 1a and 1b) is the most prevalent genotype worldwide, with a higher prevalence of 1a in the U.S. and 1b in Europe. SAPPHIRE-I is the first of six phase III trials supporting AbbVie's investigational 3D regimen for the treatment of GT1 hepatitis C patients.
"SAPPHIRE-I demonstrates that patients new to therapy with genotype 1 HCV achieved high rates of virologic response with AbbVie's interferon-free, all-oral 3D regimen plus ribavirin, and the SVR rate is consistent with results from our phase II studies," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "SAPPHIRE-I is the first of these studies to report results, and based on the progress of our clinical program to date, we are on track for major regulatory submissions in the second quarter of 2014."
AbbVie will disclose detailed SAPPHIRE-I results at future scientific congresses and in publications.
About Study M11-646 (SAPPHIRE-I)
SAPPHIRE-I is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with ABT-333 (250mg), ribavirin (weight-based), both dosed twice daily, and the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg) and dosed once daily in non-cirrhotic, GT1a and GT1b HCV-infected, treatment-naive adult patients.
The study population consisted of 631 GT1 treatment-naive patients with no evidence of liver cirrhosis with 473 patients randomized to the 3D regimen plus ribavirin for 12 weeks, and 158 patients randomized to placebo for the initial 12 weeks. Patients initially randomized to placebo for the first 12 weeks then received open-label treatment with the 3D regimen plus ribavirin for 12 weeks.
Following 12 weeks of treatment with AbbVie's 3D regimen plus ribavirin, 96 percent (n=455/473) of patients achieved SVR12 based on intent-to-treat analysis where patients with missing values for any reason were considered treatment failures. In the active treatment arm, patients with GT1b infection achieved 98 percent SVR12 (148/151), while patients with GT1a achieved 95 percent SVR12 (307/322).
The most commonly reported adverse events in the 3D and placebo arms, respectively, were fatigue, headache and nausea. Discontinuations due to adverse events were reported in 0.6 percent of patients receiving the 3D regimen and 0.6 percent of patients receiving placebo. The rate of virologic relapse or breakthrough was low, occurring in 1.7 percent of patients receiving the 3D regimen.
Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.
AbbVie's HCV Development Program
The clinical program supporting our 3D regimen includes more than 2,300 genotype 1 patients in greater than 25 countries around the world. The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral 3D regimen with or without ribavirin with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis. Results from the remaining five studies in AbbVie's phase III program will be available in the coming months, supporting regulatory submissions starting in the second quarter of 2014.
Overview of AbbVie's phase III clinical programs is as follows:
The 3D regimen consists of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's investigational 3D regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA).
ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.
Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.
There are special safety considerations when prescribing these drugs in approved populations.
Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.
Ribavirin monotherapy is not effective for the treatment for chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, automimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score >6.
See approved product labels for more information.
About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.
Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.
Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.
[1] Comparison based on review of data from clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013
[2] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.
Press Release
AbbVie Releases First of Six Phase III Results from Investigational All-Oral, Interferon-Free, 12-week Regimen, Showing 96 Percent SVR12 in Genotype 1 Hepatitis C Patients New to Therapy
- Confirms results of phase II studies, with consistent virologic response and tolerability profile
- Largest all-oral, interferon-free clinical program in genotype 1 (GT1) patients to date(1)
- On track for major regulatory submissions in Q2 2014
- Worldwide, about 160 million people are chronically infected with hepatitis C(2), most with GT1
Nov 18, 2013
NORTH CHICAGO, Ill., Nov. 18, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) released the first phase III results for the investigational three direct-acting-antiviral (3D) regimen plus ribavirin in patients chronically infected with genotype 1 (GT1) hepatitis C virus (HCV). In the 631-patient SAPPHIRE-I study, patients new to therapy receiving 12 weeks of AbbVie's 3D regimen achieved a sustained virologic response at 12 weeks post-treatment (SVR12) of 96 percent. The majority of patients were GT1a, considered the more difficult-to-treat subtype, and the SVR12 rates of GT1a and GT1b were 95 percent and 98 percent, respectively. The rate of virologic relapse or breakthrough was low, occurring in 1.7 percent of patients receiving the 3D regimen. In addition, discontinuation rates due to adverse events were low, and of an equal percentage (0.6 percent) in both active and placebo groups.
"SAPPHIRE-I demonstrates that patients new to therapy with genotype 1 HCV achieved high rates of virologic response with AbbVie's interferon-free, all-oral 3D regimen plus ribavirin, and the SVR rate is consistent with results from our phase II studies," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "SAPPHIRE-I is the first of these studies to report results, and based on the progress of our clinical program to date, we are on track for major regulatory submissions in the second quarter of 2014."
AbbVie will disclose detailed SAPPHIRE-I results at future scientific congresses and in publications.
About Study M11-646 (SAPPHIRE-I)
SAPPHIRE-I is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with ABT-333 (250mg), ribavirin (weight-based), both dosed twice daily, and the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg) and dosed once daily in non-cirrhotic, GT1a and GT1b HCV-infected, treatment-naive adult patients.
The study population consisted of 631 GT1 treatment-naive patients with no evidence of liver cirrhosis with 473 patients randomized to the 3D regimen plus ribavirin for 12 weeks, and 158 patients randomized to placebo for the initial 12 weeks. Patients initially randomized to placebo for the first 12 weeks then received open-label treatment with the 3D regimen plus ribavirin for 12 weeks.
Following 12 weeks of treatment with AbbVie's 3D regimen plus ribavirin, 96 percent (n=455/473) of patients achieved SVR12 based on intent-to-treat analysis where patients with missing values for any reason were considered treatment failures. In the active treatment arm, patients with GT1b infection achieved 98 percent SVR12 (148/151), while patients with GT1a achieved 95 percent SVR12 (307/322).
The most commonly reported adverse events in the 3D and placebo arms, respectively, were fatigue, headache and nausea. Discontinuations due to adverse events were reported in 0.6 percent of patients receiving the 3D regimen and 0.6 percent of patients receiving placebo. The rate of virologic relapse or breakthrough was low, occurring in 1.7 percent of patients receiving the 3D regimen.
Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.
AbbVie's HCV Development Program
The clinical program supporting our 3D regimen includes more than 2,300 genotype 1 patients in greater than 25 countries around the world. The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral 3D regimen with or without ribavirin with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis. Results from the remaining five studies in AbbVie's phase III program will be available in the coming months, supporting regulatory submissions starting in the second quarter of 2014.
Overview of AbbVie's phase III clinical programs is as follows:
Study
|
Patients (N)
|
Treatment Regimen
|
Treatment Duration
|
SAPPHIRE-I
|
GT1, treatment-naive
(631)
|
• ABT-450/rb +ABT-267c
• ABT-333
• Ribavirin
|
12 weeks
|
• Placebo
|
12 weeks, then active treatment for 12 weeks
| ||
SAPPHIRE-II
|
GT1, treatment-experienced
(400a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• Placebo
|
12 weeks, then active treatment for 12 weeks
| ||
PEARL-II
|
GT1b, treatment-experienced
(210 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
|
12 weeks
| ||
PEARL-III
|
GT1b, treatment-naive
(400 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
• Placebo
|
12 weeks
| ||
PEARL-IV
|
GT1a, treatment-naive
(300 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
• Placebo
|
12 weeks
| ||
TURQUOISE-II
|
GT1, treatment-naive and treatment-experienced (with compensated cirrhosis)
(380 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
24 weeks
|
a projected study population
|
b ABT-450/ritonavir
|
c ABT-267 is co-formulated with ABT-450/r, administered as two pills once daily
|
The 3D regimen consists of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's investigational 3D regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA).
ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.
Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.
There are special safety considerations when prescribing these drugs in approved populations.
Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.
Ribavirin monotherapy is not effective for the treatment for chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, automimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score >6.
See approved product labels for more information.
About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.
Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.
Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.
[1] Comparison based on review of data from clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013
[2] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.
SOURCE AbbVie
For further information: Media, Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com, or Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com; or Investor Relations, Elizabeth Shea, +1 (847) 935-2211, elizabeth.shea@abbvie.com
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